Hydrogels of quadrol methacrylate polymers

ABSTRACT

Acrylate and methacrylate monoesters and diesters having the following formula (I) ##STR1## wherein R 1 , R 2 , R 3  are as defined in the specification, are disclosed. These monomers are polymerizable into hydrogel polymers which are extremely hydrophilic. These hydrogel polymers are useful in the preparation of wound dressings. These polymers form complexes with polyvalent metal ions such as Ca, Mg, Mn and Cu, and possess macrophage stimulating activity in addition to the useful properties possessed by other acrylate and methacrylate hydrogel polymers.

TECHNICAL FIELD

This invention relates to acrylate and methacrylate monoesters anddiesters of cetain diaminopolyhydroxy compounds, and to hydrogelsprepared therefrom.

BACKGROUND ART

Quadrol, N,N,N'N'-tetrakis(2-hydroxypropyl)ethylenediamine, is oftenused as a cross-linking agent and catalyst in the synthesis of urethanefoams and as an analytical reagent for the quantitative determination ofMn³⁺. Quadrol forms complexes with other polyvalent metal ions, e.g.,cobalt, copper (II) and zinc. Recently applicants and coworkers havefound that Quadrol possesses immunological activity. When mousemacrophages are exposed to Quadrol in vitro, the macrophages are rapidlystimulated as measured by increased phagocytosis and spreading. Thisstimulation was shown to be both time and concentration dependent. Thesefindings are reported in M. V. Bhide et al, Journal ofImmunopharmacology, vol. 7, no. 3, pp. 303-312 (1985).

Quadrol can be prepared by reacting one mol of ethylenediamine with 4mols of propylene oxide as described in U.S. Pat. No. 2,697,113 toLundsted et al.

U.S. Pat. No. 3,868,409 discloses, inter alia, the monomers obtained byreacting either 3 or 4 moles of glycidyl methacrylate withethylenediamine, and polymers thereof. The monomers are trifunctional ortetrafunctional, depending on the number of moles of glycidylmethacrylate reacted, and are capable of a high degree of cross-linking.Polymers formed from these monomers are highly cross-linked, rigid andbrittle. Also disclosed are other polymers formed by reaction ofglycidyl methacrylate and other epoxy compounds with various monoamines,diamines and polyamines. Patentee characterizes his polymers as havingexceptionally high strength, and as bonding strongly to metals.

Hydrogel polymers of certain methacrylate monomers, notably2-hydroxyethyl methacrylate (HEMA), are well known. HEMA polymers arewidely used in the manufacture of contact lenses and also have beenreported as being useful in other biomedical and surgical applications.HEMA is capable of homopolymerizing and copolymerizing with othermethacrylates to form three-dimensional hydrophilic polymer (hydrogel)networks. References disclosing HEMA polymers include, for example, D.E. Gregonis et al, "Hydrogels For Medical And Related Applications",American Chemical Society Symposium, Series No. 31, edited by J. D.Andrade, August 1976, pages 88-104, and M. F. Refojo et al, Journal ofApplied Polymer Science, vol. 9, pages 2425-2435 (1965). M. F. Refojo,J. Applied Polymer Sci., vol. 9, pp 3161-3170 (1965) discloses hydrogelsprepared from glyceryl methacrylate.

U.S. Pat. No. 3,220,960 to Wichterle et al discloses hydrogelsconsisting essentially of 20-97 percent of an aqueous liquid and across-linked hydrophilic polymer. Uses for hydrogels obtained fromvarious derivatives of acrylic and methacrylic acids include dialysismembranes, diaphragms, contact lenses and other uses where prolongedcontact with body tissues is required.

Wound dressings incorporating certain hydrogels have been described inthe literature. Agar-acrylamide hydrogels and their use in wounddressings are described, for example in B. Kickhoefer et al,Biomaterials, vol. 7, pages 67-72 (1986).

DISCLOSURE OF THE INVENTION

An object of this invention is to provide novel monofunctional andbifunctional acrylate and methacrylate monomers which are polymerizableinto hydrogel polymers.

Another object of this invention is to provide novel acrylate andmethacrylate hydrogel polymers.

A more specific object of this invention is to provide novel acrylateand methacrylate hydrogel polymers which are useful in biomedicalapplications.

The novel monomers of this invention have the following formula (I)##STR2## wherein R₁ is a divalent hydrocarbon radical containing from 2to about 6 carbon atoms; R₂ is hydrogen, methyl or ethyl; R₃ is hydrogenor methyl; and Y is ##STR3##

In preferred embodiments of this invention, R₁ is ethylene (i.e. --CH₂CH₂ --), R₂ and R₃ are methyl, and Y is ##STR4##

The novel polymers of this invention are hydrogel polymers (includingcopolymers) of the novel monomers described above.

Hydrogel polymers of this invention are biologically active; inparticular they possess macrophage stimulation activity. As aconsequence, these polymers are useful as wound dressings. The polymersof this invention are useful as chelating agents for polyvalent metalions, such as copper, calcium, magnesium, manganese and zinc. These assustained and controlled for release devices, e.g., release of metalions and medications into wounds.

BEST MODE FOR CARRYING OUT INVENTION

The monomers of this invention may be either monofunctional orbifunctional, i.e., they may have either one or two acrylate ormethacrylate groups per molecule.

Monofunctional monomers may be prepared by a first general method, andbifunctional monomers by a second general method as will now bedescribed in detail.

The first reaction step in preparing both monofunctional andbifunctional monomers is to react an aliphatic diamine having theformula (II)

    H.sub.2 NR.sub.1 NH.sub.2                                  (II)

with an alkylene oxide having the formula (III) ##STR5## thereby formingan N,N'-bis(2-hydroxyalkyl)alkylenediamine compound of the formula (IV)##STR6##

The aliphatic diamines of the formula (II) contain from 2 to about 6carbon atoms. The nitrogen atoms are attached to different carbon atoms,preferably to the two end carbon atoms, in which case R₁ is a straightchain alkylene group. Suitable aliphatic diamines includeethylenediamine, propylenediamine (1,2-diaminopropane),trimethylenediamine (1,3-diaminopropane), tetramethylenediamine(1,4-diaminobutane), 1,3-diamino-1-methylpropane,1,3-diamino-2-methylpropane, pentamethylenediamine (1,5-diaminopentane),1,4-diamino-1-methylbutane, 1,4-diamino-2-methylbutane,1,3-diamino-2,2-dimethylpropane, hexamethylenediamine(1,6-diaminohexane), 1,4-dimethylbutane, and1,3-diamino-1,1,2-trimethylpropane. The preferred aliphatic diamine isethylenediamine.

Suitable alkylene oxides of the formula (III) are ethylene oxide,propylene oxide (which is preferred), and butylene oxide.

The reaction between the aliphatic diamine and the alkylene oxide may becarried out by adding the latter dropwise to the former, either neat orin a suitable solvent such as absolute ethanol. The reaction temperaturemay range from about 20° C. up to the boiling point of the amine (ifneat) or solution, and may exceed the boiling point of the alkyleneoxide. The materials react in stoichiometric proportions; tus, two molsof alkylene oxide per mol of aliphatic diamine are required.

When propylene oxide is reacted with ethylene diamine, the reactionproduct is N,N'-bis(2-hydroxypropyl)ethylenediamine, (IV-a), which isthe preferred compound of the formula (IV).

The second step in the preparation of monoacrylates andmonomethacrylates according to the first general method is to react thecompound of the formula (IV) with a further quantity of alkylene oxide(III) thereby forming an N,N,N'-tris(2-hydroxyalkyl)alkylenediamine ofthe following formula (V) ##STR7##

The alkylene oxide used in this step may be the same as or differentfrom the alkylene oxide used in the first step. Preferably the samealkylene oxide is used in both steps. The alkylene oxide may be addeddropwise to a solution of the disubstituted diamine (IV) until thestoichiometric quantity, which is one mol of alkylene oxide per mol ofdisubstituted diamine (IV), has been added. An inert solvent, e.g., amixed solvent consisting of absolute ethanol, methanol and water, may beused. The reaction temperature may range from about 20° C. up to theboiling point of the solution, although an elevated temperature ispreferred. After addition of the alkylene oxide is complete, thereaction mixture may be cooled and the product (V) separated fromunreacted disbustituted diamine (IV) by conventional means.

Reaction of N,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) withpropylene oxide yields N,N,N'-tris(2-hydroxypropyl)ethylenediamine(V-a).

It is desirable to prepare the trisubstituted diamine (V) indirectlyfrom a disubstituted diamine (IV) instead of directly from an aliphaticdiamine (II) because of the difficulty in separating by-products. Forexample, N,N,N'-tris(2-hydroxypropyl)ethylenediamine (V-a) should besynthesized in two steps via N,N'-bis(2-hydroxypropyl)ethylenediamine(IV-a) rather than directly from ethylenediamine, because of thedifficulty in the separation of side reaction products and unreactedN,N'-bis(2-hydroxypropyl)ethylenediamine from the trisubstituted product(V-a).

The final step in the first general method is to react thetrisubstituted diamine (V) with either glycidyl acrylate or methacrylateto form the product monoacrylate or monomethacrylate, which has thefollowing formula (VI) ##STR8##

Glycidyl methacrylate is ordinarily preferred, since in general thepreferred hydrogel polymers are the methacrylates.

Reaction of the trisubstituted diamine (V) with glycidyl acrylate ormethacrylate may be carried out by adding the latter to the former atambient temperature. The reaction is carried out in an inert solvent,e.g. methylene dichloride or methanol.

It is desirable to add a polymerization inhibitor, e.g. 4-methoxyphenol,to the reaction medium. The product (VI) may be recovered from thereaction mixture by conventional means.

In a preferred embodiment according to the first general method,N,N,N'-tris(2-hydroxypropyl)ethylenediamine (V-a) is reacted withglycidyl methacrylate to form Quadrol methacrylate (VI-a).

The first step in the preparation of diacrylates and dimethacrylatesaccording to the second general method is to prepare a disubstituteddiamine (IV) from an aliphatic diamine (II) and an alkylene oxide (III)as above described. In particular,N,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) may be prepared fromethylenediamine and propylene oxide.

The second and final step in the second general method is to react thedisubstituted diamine (IV) with either glycidyl acrylate or glycidylmethacrylate, depending on whether a diacrylate or a dimethacrylate isdesired. Suitable solvents and reaction conditions are generally similarto those used in the analogous preparation of monoacrylates andmonomethacrylates (VI) from a trisubstituted diamine (V), although aslightly lower temperature, e.g. about 20° C., may be maintained whilethe glycidyl acrylate or methacrylate is being added. The productdiacrylate or dimethacrylate has the following formula (VII) ##STR9##

In a preferred embodiment according to the second general method,glycidyl methacrylate is added to a solution ofN,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) to form Quadroldimethacrylate (VII-a).

It will be noted that the monomers of the general formula (I) includethe monofunctional monomers of the formula (VI) and the difunctionalmonomers of the formula (VII).

It will also be noted that both the monoacrylates and monomethacrylatesof the formula (VI) and the diacrylates and dimethacrylates of theformula (VII) are prepared by reaction of the corresponding substitutedalkylenediamine of the formula (VIII) ##STR10## when n is 1 or 2, witheither glycidyl acrylate or glycidyl methacrylate. It will also be notedthat formula (VIII) embraces formulas (IV) and (V), the formula (IV)compounds being those of formula (VIII) wherein n=1, and the formula (V)compounds being those of formula (VIII) wherein n=2.

Acrylate and methacrylate monomers of this invention are soluble inwater and common organic solvents. Thus, Quadrol methacrylate andQuadrol dimethacrylate are soluble in water, ethanol, ether andmethylene dichloride. The water solubility of these monomers is highlyadvantageous in carrying out aqueous phase polymerizations.

Monomers of this invention are polymerizable in the presence of aconventional polymerization initiator, e.g. a redox catalyst or a freeradical initiator, either in aqueous solution or in bulk. The amount ofmonomer can range from about 20 percent to nearly 100 percent of thetotal weight of the polymerization medium. Conventional redox catalysts,e.g. a redox catalyst system of ammonium persulfate and sodiummetabisulfite, can be used for solution polymerization. The amount ofcatalyst required is small, usually less than 2 percent by weight basedon the total weight of reaction medium. A small amount of apolymerization initiator (or free radical initiator), e.g.tetrabutylperoxypivalate or azobis(isobutyronitrile) (AIBN) may beadvantageously used in lieu of a redox catalyst in bulk polymerizationor in polymerization in an organic solvent. Monomers of this inventionmay be autocatalytic.

Monofunctional monomers of this invention (formula VI) can behompolymerized, copolymerized with one or more additional monofunctionalcomonomers (2-hydroxyethyl methacrylate, for example), or cross-linked.The cross-linking agent can be a bifunctional monomer of this invention(formula VIII) and in particular Quadrol dimethacrylate (VII-a).Conventional cross-linking agents, such as tetraethyleneglycoldimethacrylate, can also be used. An advantage of using a bifunctionalmonomer of this invention and in particular Quadrol dimethacrylate isthe greater hydrophilicity of the resulting hydrogel polymers. Polymersof Quadrol methacrylate cross-linked with Quadrol dimethacrylate, forexample, are more hydrophilic than polymers of Quadrol methacrylatecross-linked with tetraethylene glycol dimethacrylate. Greater watersolubility allows the use of higher monomer concentrations in an aqueouspolymerization medium without sacrificing clarity in the polymerproduct. The amount of cross-linking agent when used is usually no morethan about 5 percent by weight, based on total monomer content, and ismore usually about 2 percent to about 4 percent by weight, based ontotal monomer content. Conventional polymerization conditions used forpreparation of known methacrylate hydrogel polymers can be used herein.

Non-cross-linked polymers of this invention are water-soluble;cross-linked polymers of this invention are in the form of hydrogels.

Polymers of this invention, whether cross-linked or not, are extremelyhydrophilic. For example, poly(Quadrol methacrylate) hydrogel,cross-linked with 4 percent by weight of tetraethylene glycoldimethacrylate, after equilibration with water, contains between 80percent and 85 percent by weight of water. Poly(Quadrol dimethacrylate)hydrogel, also cross-linked with 4 percent by weight oftetraethyleneglycol dimethacrylate, contains over 90 percent by weightof water at equilibrium.

Polymers of this invention are also non-toxic.

Non-cross-linked polymers of this invention are chelating agents. Theyform complexes with polyvalent metal ions, such as copper, calcium,magnesium, manganese and zinc. For example, poly(Quadrol methacrylate)forms a 1:1 (mol ratio) complex with the cupric ion. The metal ions canbe completely removed from these complexes by dialysis with anappropriate material such as a buffered EDTA (ethylenediaminetetraacetic acid) solution.

Polymers of this invention are biologically active. In particular, theyhave macrophage stimulation activity. In other words, the polymers ofthis invention stimulate the activity of macrophages in the bodies ofhumans and other warm blooded animals, so that they more effectivelyperform their functions, for example, that of removing and consumingbacteria and other foreign bodies in the body of the host animal.Cross-linked polymers of this invention are particularly useful inbiomedical applications because of their physical form; as hydrogelsthey swell but do not dissolve in water.

Polymers of this invention, especially cross-linked polymers, are usefulas wound dressings. They may be applied to the skin of the animal at thewound or lesion site in the same way as polymeric wound dressings nowknown. By virtue of their macrophage stimulation activity, polymericwound dressings of this invention stimulate the activity of macrophagesat the wound site, thereby accelerating wound healing. Furthermore, theinvention wound dressings perform their function without being absorbedinto the bloodstream of the host. As a consequence, there are no sidereactions and a dressing can remain in place for a long period of time,with changes only at infrequent intervals. In contrast, presently knownwound dressings merely protect the wound from infection and foreignmatter (a function which the invention wound dressings also perform) and(where desired) serve as carriers for pharmacological agents withouthaving any biological activity of their own.

These polymers may also be used as carriers for biologically activeagents. For example, biologically important metal ions such as calcium,magnesium, manganese or zinc may be supplied to a wound by preparing apolymer/metal ion complex as above described, placing this complex overthe wound, and supporting the complex with a conventional bandage. Themetal ion is released gradually and in a controlled basis into thewound. Other controlled release wound dressings can be prepared in asimilar manner. The only requirement is that the biologically activematerial must be absorbable by the polymer and slowly releasabletherefrom.

Polymers of this invention can also be formed into soft contact lenses.These polymers, incorporating a biologically active agent, areparticularly useful for controlled release of a medication into the eye.

Polymers of this invention are also useful for the same purposes aspresently known methacrylate hydrogel polymers such as 2-hydroxypropylmethacrylate.

Copolymers of this invention (e.g., a copolymer of Quadrol methacrylateand a hydrophilic comonomer such as 2-hydroxyethyl methacrylate, with orwithout a cross-linking agent) in general have the same utilities as thecorresponding invention homopolymers.

Bifunctional monomers of this invention are particularly useful ascross-linking agents for hydrophylic monofunctional monomers, includingmonomers of this invention (Quadrol methacrylate, for example) as wellas known monomers (e.g., 2-hydroxyethyl methacrylate). They are used insmall amounts, typically about 2 to 5 percent by weight, based on totalmonomer weight. An advantage of cross-linking a monofunctional monomerof this invention (e.g., Quadrol methacrylate) with a bifunctionalmonomer of this invention (e.g., Quadrol dimethacrylate) rather than aconventional bifunctional monomer (e.g., tetraethyleneglycoldimethacrylate) is that higher monomer solids contents can be used inaqueous polymerization, due to greater hydrophilicity of thecross-linked polymer present as polymerization proceeds. Thesedifunctional monomers can also be used as starting materials forhomopolymerization or for copolymerization with known monofunctional ordifunctional hydrophilic monomers, e.g. 2-hydroxyethyl methacrylate andtetraethylene glycol dimethacrylate, respectively.

A particularly desirable characteristic of the polymers of thisinvention is that their actual and potential uses go beyond those ofpresently known hydrogel polymers. Varius biomedical applications havebeen particularly noted in this regard.

The invention will now be described further with respect to specificembodiments thereof, as illustrated in the examples which follow. Allparts are by weight unless otherwise indicated.

EXAMPLE 1 N,N'-Bis(2-hydroxypropyl)ethylenediamine

(IV-a): Propylene oxide (142.4 g, 2.4 mol) was added dropwise over aperiod of 11 hours to a solution of ethylenediamine (71.9 g, 1.2 mol) in25 mL absolute ethanol and 10 mL of nitrogen purged distilled water at90° C. After addition, the reaction was maintained for an additionalhour, then cooled to room temperature (about 20° C.). The reactionsolution was concentrated by rotary evaporation to give a milky whitesuspension which, upon dissolution in anhydrous ether, produced a whiteprecipitate of N,N'-bis(2-hydroxypropyl)ethylenediamine in 28.5 percentyield. The product was crystallized from methanol/ethanol [m.p. 132° C.,IR(Nujol):3250(OH); NMR(MeOHd₄): δ3.8(m, 2H); 2.6(t, 8H); 1.2(d, 6H)].

EXAMPLE 2 N,N,N'-tris(2-hydroxypropyl)ethlenediamine

(V-a): Propylene oxide (181.6 g, 0.3 mol) in 25 mL of absolute ethanolwas added dropwise for 4.5 hours to a solution ofN,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) (55 g, 0.3 mol) in 50 mLeach of absolute ethanol, methanol and distilled water at 80° C. Thereaction mixture was cooled and concentrated to give a milky whiteviscous suspension. The suspension was dissolved in ether and dried overanhydrous sodium sulfate. Unreacted (IV-a) precipitated and was removedby filtration. Ether was removed from the clear filtrate to produce aviscous liquid. Fractional distillation of the oil producedN,N,N'-tris(2-hydroxypropyl)ethylenediamine [bp. 140° C. at 0.15 mm;yield 55 percent; IR(neet): 3350(broad OH); NMR(CDCl₃): δ 3.8(broad m,3H); 2.5(broad m, 10H); 1.1(d, 9H)].

EXAMPLE 3 Quadrol methacrylate

(VI-a): Glycidyl methacrylate (5.0 g, 35.5 mmol) was added, dropwise, toa solution of N,N,N'-tris(2-hydroxypropyl)ethylenediamine (V-a) (8.3 g,35.5 mmol) in 10 mL of CH₂ Cl₂ at room temperature. 4-Methoxyphenol(0.03 g) was added to prevent polymerization. The reaction wasmaintained for 72 hours at room temperature, then warmed to 30° C. foran additional 24 hours. The reaction was followed by TLC (4 percent MeOHin CCl₄ ; glycidyl methacrylate R_(f) 0.69). Quadrol methacrylate (VI-a)was obtained in quantitative yield after removal of the solvent. Theproduct was further purified by dissolving 5 g of (VI-a) in 200 mLdistilled water followed by addition of sodium chloride to saturation.The product, which separated out as an oil, was collected, dissolved inCH₂ Cl₂, and dried over anhydrous magnesium sulfate. After filtration,the solvent was removed to give Quadrol-methacrylate [yield, 53 percent;IR(neet):3350(broad OH); 1720(C═O); 1640(C═C); NMR(CDCl₃ ): δ6.2(s, 1H);5.6(s, 1H); 4.0(broad m, 6); 2.5(broad m, 12H); 2.0 (s, 3H); 1.1(d,9H)].

EXAMPLE 4 Quadrol dimethacrylate

(VII-a): Glycidyl methacrylate (4.8 g, 34 mmol) and 4-methoxyphenol(0.13 g) were added to a solution ofN,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) (3.0 g, 17 mmol) in 80mL of methanol at 0° C. The mixture was brought to room temperature andmaintained for eight days, followed by heating for 24 hours at 30° C. Aquantitative yield of a viscous, slightly brown liquid was obtainedafter removal of the solvent. The product was further purified bydissolving the liquid in water followed by the addition of sodiumchloride to saturation. The oil layer was separated, dissolved in CH₂Cl₂ and dried over magnesium sulfate. Filtration and removal of solventyielded Quadrol dimethacrylate (VII-a) [yield 48 percent;IR(neet):3350(broad OH); 1700 (C═O); 1620(C═C); NMR(CDCl₃): δ6.1(s, 2H);5.6(s, 2H); 3.8(broad m, 8H); 2.6(broad m, 12); 2.0(s, 6H); 1.1(d, 6H)].

EXAMPLE 5

20 parts of Quadrol methacrylate (VI-a) were dissolved in 78.4 parts ofdistilled water in a glass mold. This solution was polymerized at roomtemperature (about 25° C.) in the presence of a redox catalyst systemcontaining 0.8 parts of ammonium persulfate and 0.8 parts of sodiumm-bisulfite. After thorough mixing, the solution was degassed twice andfinally put into a vacuum oven for 12 hours at room temperature. Theclear, tacky polymer was post heated at 55°-60° C. for 24 hours beforeuse.

EXAMPLE 6

65.0 parts of Quadrol dimethacrylate (VII-a), 27.2 parts of distilledwater and 2.6 parts of tetrethyleneglycol methacrylate were mixed in aglass mold. The homogenous solution was polymerized using a redoxcatalyst system containing 2.6 parts of ammonium persulfate and 2.6parts of sodium m-bisulfite as described in Example 5.

EXAMPLE 7

95.7 parts of Quadrol dimethacrylate (VI-a) were mixed with 3.8 parts ofcold tetraethyleneglycol methacrylate in a glass mold. This slightlyviscous solution was bulk polymerized at room temperature by mixing with0.47 parts of cold tetrabutylperoxypivalate. The water equilibratedpolymer had a physical form similar to that of a soft contact lens.

EXAMPLE 8

35.8 parts of Quadrol methacrylate were dissolved in 63.4 parts of colddistilled water. This solution was mixed with various amounts oftetraethyleneglycol dimethacrylate ranging from 0.35 parts to 4.1 parts.The polymerizations were carried out using redox catalyst systemcontaining 0.72 parts of ammonium persulfate. The tacky hydrogels, uponequilibration with water gave hydrated hydrogels containing 90 to 96percent by weight water.

Example 8 was repeated using 66.7 parts of Quadrol methacrylate, and 2or 4 parts of tetraethylene glycol, and 33.3 parts of water as thestarting solution. The resulting hydrogels contained about 83 to 86percent by weight of water.

EXAMPLE 9

15.9 parts of 2-hydroxyethyl methacrylate, 47.8 parts of Quadrolmethacrylate (VI-a) and 1.2 parts of tetrethyleneglycol dimethacrylatewere dissolved in 31.5 parts of cold distilled water in a glass mold.The solution was polymerized in the presence of redox catalyst systemcontaining 1.7 parts of each of ammonium persulfate and sodiumm-bisulfite as described in Example 5.

EXAMPLE 10

35.4 parts of Quadrol dimethacrylate (VII-a) and 1.4 parts oftetraethyleneglycol dimethacrylate were mixed with 70 parts of colddistilled water. The slightly hazy solution was polymerized as describedin Example 5 using 2.1 parts of ammonium persulfate as a redoxinitiator.

EXAMPLE 11

Polymerization of Quadrol methacrylate (VI-a) was carried out in a 50 mlround bottom flask fitted with a mechanical stirrer, a thermometer, anitrogen inlet, an addition funnel and a drying tube.

10.0 mls of dimethylformamide (dried and distilled over sodium hydride)was brought to 70° C. in a reaction flask under nitrogen atmosphere.3.2442 g of Quadrol methacrylate (VI-a) and 0.0324 g ofN,N'-azobis(isobutyronitrile) (AIBN) were dissolved in 7 mls of driedDMF in a pressure equalizing addition funnel. This solution was added tothe reaction flask with mechanical agitation. The reaction was allowedto proceed at 70° C. for two hours at which time 0.0032 g of AIBNdissolved in 2 mls of DMF was added to the reaction. At the end ofadditional one hour, polymer was isolated as a clear paste by removal ofDMF under reduced pressure.

The polymer was dissolved in 10 mls of a 50:50 mixture of distilledwater and methanol. The clear solution was dialyzed against 3000 mls of50:50 mixture of H₂ O:CH₃ OH using 2000 molecular weight cut-offdialysis tubing. The dialyzing solution was changed every 24 hours overa total dialysis period of 3 days. Finally, the solution was dialyzedagainst 4000 mls of methanol. The polymer solution was taken out of thetube, filtered and methanol was removed under reduced pressure to yieldwhite shiny polymer. It was dissolved in methylene chloride, dried overmagnesium sulfate, filtered and recovered again as a fluffy, veryhygroscopic material in 42 percent yield based on monomer weight.

The polymer was readily soluble in chlorinated hydrocarbons, water,dimethylsulfoxide, dimethylacetamide, acetone, methanol, ethanol,tetrahydrofuran and insoluble in toluene, benzene and hexane. Itsinherent viscosity (Cannon-Fenske) in tetrachloroethane at 30° C. was0.10 g./dl (0.5 g/100 ml of solvent). The number average molecularweight of the polymer using a Knauer vapor pressure osmometer was10,135. Thermogravimetric analysis of the polymer on a Dupont 1090thermal analyzer indicated a glass transition temperature of 32° C.

EXAMPLE 12 Copper(II) complexation with poly(Quadrol methacrylate)hydrogel (PQM)

Poly(Quadrol methacrylate)(PQM) hydrogel was prepared and exhaustivelyswelled and dialyzed (Spectropor dialysis tubing, 10,000 MWCO) to removeunreacted monomer. The hydrogel was then treated with increasingconcentrations of copper (II) chloride. The absorbance maximum for theQuadrol:Cu complex at 675 nm was monitored following the methods of Hallet al. as described in the Journal of the American Chemical Society,vol. 79, page 3361 (1957). Absorbance of a 0.226 millimol solution ofquadrol in PQM was found to increase linearly with increasing amounts of0.1 molar cupric chloride solution until the [Cu⁺⁺ ]/[Quadrol in PQM]concentration ratio reached about 1.0 (molar ratio). Absorbance thenleveled off quickly with further increases in copper ion concentration,and reached a maximum at a [Cu⁺⁺ ]/[Quadrol in PQM] ratio of 1.5.

EXAMPLE 13

Polymer made in Example 5 was allowed to dissolve in distilled water.The resulting slightly viscous solution was dialyzed against a largevolume of phosphate buffered saline (pH 7.2) using 2000 molecular weightcut-off dialysis tubing to remove redox catalysts, unreacted Quadrolmethacrylate and low molecular weight oligomers. The biological activityof the buffered poly(Quadrol methacrylate) solution was assayed bymeasuring in vitro phagocytosis of polystyrene beads following theprocedures of M. V. Bhide, et al, Journal of Immunopharmacology, vol 7,no. 3 (1985), pp. 303-308. The phagocytosis was found to be 53 percentfor control (phosphate buffered saline) and 68 percent for poly(Quadrolmethacrylate).

While this invention has been described with reference to specificembodiments thereof, it is apparent that the invention is not limitedthereto and that various modifications can be made without departingfrom the scope of this invention.

What is claimed is:
 1. A hydrogel comprising:(A) a crosslinked polymerof a major amount of compound of the formula (I) ##STR11## wherein R₁ isa divalent hydrocarbon radical containing from 2 to about 6 carbonatoms; R₂ is hydrogen, methyl or ethyl; R₃ is hydrogen or methyl; and Yis ##STR12## and (B) water.
 2. A hydrogel according to claim 1 whereinsaid polymer is a polymer of a major amount of said compound of theformula (I) and a minor amount of one or more hydrophilic comonomers. 3.A hydrogel according to claim 1, said hydrogel having an equilibriumwater content of at least about 80 percent by weight.
 4. A hydrogelaccording to claim 1 wherein said polymer is a crosslinked polymer of amajor amount of Quadrol momomethacrylate.
 5. A hydrogel according toclaim 1 wherein said polymer is a crosslinked polymer of a major amountof Quadrol dimethacrylate.
 6. A hydrogel according to claim 1 wherein Yis ##STR13##
 7. A hydrogel according to claim 1 wherein Y is ##STR14##